Phosphonates, process for preparing the same and medicaments

ABSTRACT

Compounds of formula I ##STR1## in which R 1 , R 2  are the same or different and denote a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an alkenyl group, an alkinyl group or an aralkyl group or R 1  and R 2  together denote an alkylene residue which, together with the bound oxygen atoms and the phosphorus atom carrying the oxygen atoms, forms a saturated 5-membered to 8-membered ring; 
     R 3  denotes an optionally substituted amino group, an alkyl group, a cycloalkyl residue or an optionally substituted aryl residue; 
     n denotes an integer between 1 and 4, 
     as well as hydrates, solvates and physiologically tolerated salts thereof, their optically active forms, processes for their production as well as pharmaceutical preparations having factor Xa-inhibitory properties which contain these compounds.

This application is a 371 of PCT/EP97/06365 filed Nov. 14, 1997.

The invention concerns new phosphonates of the general formula I##STR2## in which R¹, R² are the same or different and denote a hydrogenatom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, analkenyl group, an alkinyl group or an aralkyl group or R¹ and R²together denote an alkylene residue which, together with the boundoxygen atoms and the phosphorus atom carrying the oxygen atoms, forms asaturated 5-membered to 8-membered ring;

R³ denotes an optionally substituted amino group, an alkyl group, acycloalkyl residue or an optionally substituted aryl residue;

n denotes an integer between 1 and 4,

as well as hydrates, solvates and physiologically tolerated saltsthereof. The invention also concerns the optically active forms,racemates and mixtures of diastereomers of these compounds.

The invention also concerns processes for the production of theabove-mentioned compounds, pharmaceutical preparations that contain suchcompounds as well as the use of these compounds in the production ofpharmaceutical preparations.

The phosphonates of the general formula I, their solvates and theirsalts intervene in the process of blood coagulation by the reversibleinhibition of factor Xa and thus they prevent formation of hyalinethrombi. They can therefore be used to combat and prevent diseases suchas thrombosis, apoplexy, coronary infarction, inflammations andarteriosclerosis.

Factor Xa is a serine protease of the coagulation system which catalysesthe proteolytic conversion of prothrombin into thrombin. Thrombin as thelast enzyme of the coagulation cascade on the one hand cleavesfibrinogen to form fibrin which becomes an insoluble gel aftercross-linking by factor XIIIa and forms the matrix for a thrombus; onthe other hand thrombin activates platelet aggregation by proteolysis ofits receptor on the blood platelets and in this way also contributes tothrombus formation. When a blood vessel is damaged these processes arenecessary in order to stop bleeding. No measurable thrombinconcentrations are present in blood plasma under normal conditions. Anincrease in the thrombin concentration can lead to the formation ofthrombi and hence to thromboembolic diseases which occur very frequentlyabove all in industrial countries. The formation of thrombin can beprevented by inhibiting factor Xa.

It has recently been reported that amidinoarylpropanoic acid derivativessuch as(+)-(2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]3-3-(7-amidino-2-naphthyl]propanoicacid-hydrochloride-pentahydrate (DX-9065a; formula IIa) inhibit factorXa (J. Med. Chem. 1994, 37, 1200-1207; Thrombosis and Haemostasis 1994,71, 314-319; EP-0-540-051-A-1). Further known factor Xa inhibitors are1,2-bis-(5-amidino-2-benzofuranyl)-ethane (DABE, formula IIb; ThrombosisResearch 1980, 19, 339-349) and also phenyl-amino-methyl-naphthamidinesof the general formula IIc (WO96/16940). ##STR3##

The new phosphonates according to the invention of the general formula Ias well as hydrates, solvates and physiologically tolerated saltsthereof are potent and selective factor Xa inhibitors.

In the general formula I the substituents R¹ and R² can be the same ordifferent.

If R¹, R² in the general formula I denote an alkyl group, this can bestraight-chained or branched and contain 1 to 6 carbon atoms. A methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexylgroup are preferred.

If R¹, R² in the general formula I denote a cycloalkyl group, this canbe substituted or unsubstituted and contain 3 to 8 carbon atoms. Acyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl group are preferred.

If R¹, R² in the general formula I denote a hydroxyalkyl group, this canbe straight-chained or branched and contain 1 to 6 carbon atoms. Ahydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyland hydroxyhexyl group are preferred.

If R¹, R² in the general formula I denote an alkenyl group, this can bestraight-chained or branched and contain 2 to 6 carbon atoms. A vinyl,1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 1-pentenyl and1-hexenyl group are preferred.

If R¹, R² in the general formula I denote an alkinyl group, this can bestraight-chained or branched and contain 2 to 6 carbon atoms. An ethinyland propargyl group are preferred.

If R¹, R² in the general formula I denote an aralkyl group, thiscontains a phenyl group linked to a straight-chained or branched C₁ -C₆alkyl chain, a naphthyl group linked to a straight-chained or branchedC₁ -C₆ alkyl chain or a biphenyl group linked to a straight-chained orbranched C₁ -C₆ alkyl chain. In this case a benzyl group, ap-phenylbenzyl group and a naphthylmethyl group are preferred.

If R¹, R² in the general formula I together denote an alkylene group,this can be straight-chained or branched and contain 2 to 6 carbonatoms. An ethylene, propylene and 2,3-dimethyl-2,3-butanediyl group arepreferred.

If R³ in the general formula I denotes an amino group, this can beunsubstituted or substituted with one or two C₁ -C₆ alkyl groupspreferably methyl or ethyl, with one or two C₃ -C₈ cycloalkyl groupspreferably cyclopropyl, cyclopentyl, cyclohexyl or cyclooctyl, with oneor two C₁ -C₆ hydroxyalkyl groups preferably hydroxyethyl orhydroxypropyl, with one or two C₃ -C₆ alkenyl groups preferably allyl,with one or two C₃ -C₆ alkinyl groups preferably propargyl or with oneor two aralkyl groups preferably benzyl. In this case the specification(C₁ -C₆) represents a straight-chained or branched alkyl chain with 1 to6 carbon atoms, (C₃ -C₈) represents a branched or unbranched cycloalkylgroup with 3 to 8 carbon atoms and (C₃ -C₆) represents either a branchedor unbranched alkenyl or alkinyl group with 3 to 6 carbon atoms.

If R³ in the general formula I denotes an alkyl group, this can bestraight-chained or branched and contain 1 to 6 carbon atoms. A methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl and hexylgroup are preferred.

If R³ in the general formula I denotes a cycloalkyl group, this can bebranched or unbranched and contain 3 to 8 carbon atoms. A cyclopropyl,cyclopentyl, cyclohexyl and cyclooctyl group are preferred.

If R³ in the general formula I denotes an aryl residue this isunderstood to include a phenyl, biphenyl or naphthyl group. The arylresidue can be unsubstituted or optionally carry one or several C₁ -C₆alkyl preferably methyl, C₁ -C₆ alkyloxy preferably methoxy or halogensubstituents. In this case the specification (C₁ -C₆) represents astraight-chained or branched alkyl chain with 1 to 6 carbon atoms.Halogens as substituents of the aryl residue can be fluorine, chlorine,bromine and iodine atoms, but preferably chlorine or bromine atoms.

The number n denotes an integer between 1 and 4.

Compounds of the general formula I are preferred in which

R¹, R² are the same or different and denote a hydrogen atom, a methylgroup, an ethyl group, a propyl group, an allyl group, a propargyl groupor a benzyl group or R¹ and R² together denote an ethylene group or apropylene group;

R³ denotes an amino group, an N-methyl-amino group, an N-benzyl-aminogroup, an N-allyl-amino group, an N,N-dimethylamino group, a methylgroup, an ethyl group, a cyclopropyl group or a 4-methoxyphenyl residueand

n can be 1 or 2.

Compounds of the general formula I are particularly preferred in which

R¹ and R² are the same and denote an ethyl group;

R³ denotes a methyl group and

n denotes the number 2.

Physiologically tolerated salts of the general formula I are understoodas for example formates, acetates, caproates, oleates, lactates or saltsof carboxylic acids with up to 18 carbon atoms or salts of dicarboxylicacids and tricarboxylic acids such as citrates, malonates and tartratesor alkanesulfonates with up to 10 carbon atoms or p-toluenesulfonates orsalicylates or trifluoroacetates or salts of physiologically toleratedmineral acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulphuric acid, phosphoric acid. The compounds of formula I withone or two free acid groups on the phosphonate fragment can also formsalts with physiologically tolerated bases. Examples of such salts arealkaline metal, alkaline-earth metal, ammonium and alkylammonium saltssuch as a sodium, potassium, calcium or tetramethylammonium salt.

The compounds of formula I can be solvated and in particular hydrated.The hydration can be achieved in the course of the production process orgradually occur as a result of hygroscopic properties of a compound offormula I which is firstly anhydrous.

The invention also concerns the optically active forms, the racematesand mixtures of diastereomers of compounds of the general formula I.

For the production of pharmaceutical preparations, the substances of thegeneral formula I are mixed with suitable pharmaceutical carriersubstances, aromatics, flavourings and dyes and are for example formedinto tablets or dragees or are suspended or dissolved in water or oile.g. olive oil with the addition of appropriate auxiliary substances.

The substances of the general formula I and their salts can beadministered enterally or parenterally in a liquid or solid form. Wateris preferably used as an injection medium which contains the usualadditives for injection solutions such as stabilizers, solubilizers orbuffers. Such additives are e.g. tartrate and citrate buffer, complexingagents (such as ethylenediaminetetraacetic acid and their non-toxicsalts) and high molecular polymers such as liquid polyethylene oxide inorder to regulate viscosity. Solid carrier materials are e.g. starch,lactose, mannitol, methylcellulose, talcum, highly dispersed silicicacids, high molecular fatty acids (such as stearic acid), animal andvegetable fats and solid high molecular polymers (such as polyethyleneglycols). Preparations suitable for oral administration can, if desired,contain flavourings and sweeteners.

The compounds are usually administered in amounts of 10-1500 mg per dayin relation to 75 kg body weight. It is preferable to administer 1-2tablets with a content of active substance of 5-500 mg 2-3 times perday. The tablets can also be retarded as a result of which only 1-2tablets with 20-700 mg active substance have to be administered per day.The active substance can also be administered by injection 1-8 times perday or by continuous infusion in which case 50-2000 mg per day areusually sufficient.

Compounds of the general formula I are produced according to knownmethods.

Compounds of the general formula I are produced by for example reactinga compound of the general formula III ##STR4## in which R¹, R² and nhave the meanings stated above, with a guanylation reagent such as1H-pyrazole-1-carboxamidine or S-methylisothiourea in an inert solventsuch as e.g. dimethylformamide, dioxane, dimethylsulfoxide or toluene attemperatures between 0° C. and the boiling point of the solvent,preferably at 0 to 30° C. in the presence of an auxiliary base such ase.g. triethylamine, N-methylmorpholine, pyridine orethyldiisopropylamine.

Compounds of the general formula I can also be produced by reactingcompounds of the general formula III, in which R¹, R² and n have themeanings given above, with appropriately substituted guanylationreagents in an inert solvent such as e.g. dimethylformamide, dioxane,dimethylsulfoxide or toluene at temperatures between 0° C. and theboiling point of the solvent, preferably at 0 to 30° C. in the presenceof an auxiliary base such as e.g. triethylamine, N-methylmorpholine,pyridine or ethyldiisopropylamine.

Compounds of the general formula I can also be produced by reactingcompounds of the general formula III, in which R¹, R² and n have themeanings given above, with aliphatic or aromatic imidic acid esterhydrochlorides in an inert solvent such as tetrahydrofuran, diethylether, ethanol, dimethylformamide or dioxane in the presence of anauxiliary base such as triethylamine, ethyldiisopropylamine orN-methylmorpholine.

Compounds of the general formula III are produced by reacting a compoundof the general formula IV, ##STR5## in which R¹, R² and n have themeanings stated above and PG¹ denotes a protective group such as e.g. abenzyloxycarbonyl group, a t-butyloxycarbonyl group or anallyloxycarbonyl group, with a protective group cleaving reagent.Protective groups are cleaved according to conventional methods (seee.g. T. W. Green, P. G. M. Wuts, Protective Groups in Organic Synthesis,2nd ed., John Wiley and Sons Inc. 1991) by acidic reagents such as e.g.hydrogen bromide in glacial acetic acid or trifluoroacetic acid oretherial HCl solution or hydrogenolytically or by palladium-catalysed orrhodium-catalysed cleavage.

Compounds of the general formula IV are produced by reacting a compoundof the general formula V, ##STR6## in which R¹, R², n and PG¹ have themeanings stated above with ammonia or ammonium salts such as e.g.ammonium acetate, ammonium chloride or ammonium oxalate in an inertsolvent such as methanol, ethanol or isopropanol at temperatures between0° C. and the boiling point of the solvent, preferably between roomtemperature and 65° C.

Compounds of the general formula V are produced by reacting a compoundof the general formula VI, ##STR7## in which R¹, R², n and PG¹ have themeanings stated above, with methylation reagents such as methyl iodideor dimethyl sulfate in an inert solvent such as methanol, ethanol,acetone or dioxane at temperatures between 0° C. and the boiling pointof the solvent, preferably between room temperature and 55° C.

Compounds of the general formula VI are obtained by treating a compoundof the general formula VII, ##STR8## in which R¹, R², n and PG¹ have themeanings stated above, with hydrogen sulfide in an inert solvent such aspyridine, methanolic ammonia solution, ethanol, chloroform ordimethylformamide at temperatures between 0° C. and the boiling point ofthe solvent, preferably between 0° C. and room temperature optionally inthe presence of an auxiliary base such as diethylamine, triethylamine,ethyldiisopropylamine or N-methylmorpholine.

Compounds of the general formula VII are produced by condensing7-hydroxynaphthalene-2-carbonitrile with a compound of the generalformula VIII, ##STR9## in which R¹, R², n and PG¹ have the meaningsstated above, in an inert solvent such as dioxane, tetrahydrofuran ortoluene in the presence of diethylazodicarboxylate andtriphenylphosphine, trimethyl or triethylphosphite at temperaturesbetween 0 and 50° C., preferably at room temperature.

7-Hydroxy-naphthalene-2-carbonitrile is known in the literature (seee.g. L. M. Tolbert, J. E. Haubrich, J. Am. Chem. Soc. 1994, 116,10593-10600) and can be prepared by the processes described therein orin other references (e.g: S. A. Jacobs, R. G. Harvey, J. Org. Chem.1983, 48, 5134-5135; V. N. Kopranenkov, E. A. Makarova, E. A.Luk'yanets, Zh. Org. Khim. 1981, 358-361; B. Basu, D. Mukherjee, J.Chem. Soc. Chem. Commun. 1984, 105-106; B. Basu, D. Mukherjee,Tetrahedon Lett. 1984, 4445-4446; S. K. Maity, D. Mukherjee, TetrahedronLett. 1983, 5919-5920).

Compounds of the general formula VIII are produced by reacting acompound of the general formula IX, ##STR10## in which n and PG¹ havethe meanings stated above with a compound of the general formula X,##STR11## in which R¹ and R² have the meanings stated above in thepresence of an auxiliary base such as triethylamine,diisopropylethylamine, N-methylmorpholine, pyridine, sodium methylate orsodium ethylate at temperatures between 0° C. and 80° C., preferably at60° C.

Compounds of the general formula X, in which R¹ and R² have the meaningsstated above, are either commercially available or known in theliterature or can be synthesized by standard methods from commercialprecursors or precursors known in the literature.

Compounds of the general formula IX are produced by condensing acompound of the general formula XI, ##STR12## in which n and PG¹ havethe meanings stated above, with 4-hydroxybenzaldehyde in an inertsolvent such as dioxane, tetrahydrofuran or toluene in the presence ofdiethylazodicarboxylate and triphenylphosphine, trimethylphosphite ortriethylphosphite at temperatures between 0 and 50° C., preferably atroom temperature.

Compounds of the general formula XI in which n and PG¹ have the meaningsstated above are either commercially available or known in theliterature or can be produced according to processes known from theliterature (see e.g. K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth.Commun. 1985, 15, 587-598; P. G. Houghton, G. R. Humphrey, D. J.Kennedy, D. C. Roberts, S. H. Wright, J. Chem. Soc. Perkin Trans.1 1993,13, 1421-1424; T. W. Green, P. G. M. Wuts, Protective Groups in OrganicSynthesis, 2nd ed., John Wiley and Sons Inc. 1991).

Certain compounds of the general formula I can be subsequently convertedinto other compounds of the general formula I.

This applies to compounds of the general formula I in which n and PG¹have the meanings stated above and R¹ and R² are the same or differentand denote an alkyl group, a cycloalkyl group, an alkenyl group, analkinyl group or an aralkyl group. These compounds can be converted intocompounds of the general formula I with a free phosphonic acid group bypartial hydrolysis e.g. with aqueous potassium hydroxide solution, withaqueous pyridine or by treatment with sodium iodide in acetone attemperatures between 0° C. and the boiling point of the solvent,preferably at reflux temperature.

This also applies to compounds of the general formula I in which n andPG¹ have the meanings stated above, R¹ denotes an alkyl group or acycloalkyl group and R² denotes a benzyl group. In this process thebenzyl group is replaced by a hydrogen atom by catalytic hydrogenationin inert solvents such as methanol, ethanol, tetrahydrofuran or dioxanein the presence of a catalyst preferably palladium on carbon. The benzylgroup can also be removed by reaction with a strong acid such astrifluoroacetic acid in the presence of mesitylene, anisole orthioanisole at temperatures between 0 and 50° C., preferably at roomtemperature or by treatment with Lewis acids such as BF₃ etherate in aninert solvent such as toluene, acetonitrile, diethyl ether ortetrahydrofuran at temperatures between 0° C. and the boiling point ofthe solvent, preferably between room temperature and the boiling pointof the solvent.

This also applies to compounds of the general formula I in which n andPG¹ have the meanings stated above, R¹ denotes an alkyl group or acycloalkyl group and R² denotes an allyl group. In this process theallyl group is replaced by a hydrogen atom by transition metal catalysedcleavage for example in the presence of a rhodium catalyst such astris-triphenylphosphine rhodium chloride or a palladium catalyst such astetrakis-triphenylphosphine palladium in an inert solvent such astetrahydrofuran or dioxane optionally in the presence of a nucleophilesuch as malonic acid diethyl ester, tributyl tin hydride,5,5-dimethylcyclohexane-1,3-dione or piperidine at temperatures between0° C. and 50° C., preferably at room temperature.

This also applies compounds of the general formula I in which n and PG¹have the meanings stated above and R¹ and R² are the same or differentand denote an alkyl group, a cycloalkyl group, a hydroxyalkyl group, analkenyl group, an alkinyl group or an aralkyl group. These compounds canbe converted into free phosphonic acids of the general formula I bytreatment with trimethylsilyl iodide or trimethylsilyl bromide attemperatures between 0° C and the boiling point of the solvent,preferably between room temperature and 50° C. in an inert solvent suchas diethyl ether, tetrahydrofuran, dimethylformamide, dichloromethane orchloroform. The phosphonic acid esters of the general formula I can alsobe completely saponified by acid hydrolysis in an aqueous medium forexample in dilute or semi-concentrated hydrochloric acid at temperaturesbetween room temperature and the boiling point of the reaction mediumpreferably at reflux temperature.

Pure enantiomers of compounds of formula I are produced either byracemate resolution (via salt formation with optically active acids orbases) or by using optically active starting materials in the synthesisor by enzymatic hydrolysis.

The following compounds are preferred within the sense of the inventionin addition to those mentioned in the examples:

1.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid diallyl ester

2.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy)-phenyl]-methyl}-phosphonicacid diethyl ester

3.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid diethyl ester

4.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid diethyl ester

5.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid monoethyl ester

6.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy)-phenyl]-methyl}-phosphonicacid monoethyl ester

7.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid monoethyl ester

8.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid monoethyl ester

9.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-propyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid monoethyl ester

10.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid

11.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy]-phenyl]-methyl}-phosphonicacid

12.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid

13.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid

14.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid dimethyl ester

15.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy)-phenyl]-methyl}-phosphonicacid dimethyl ester

16.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid dimethyl ester

17.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid dimethyl ester

18.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid monomethyl ester

19.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy)-phenyl]-methyl}-phosphonicacid monomethyl ester

20.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid monomethyl ester

21.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid monomethyl ester

22.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-propyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid monomethyl ester

23.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid dipropyl ester

24.((7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy)-phenyl]-methyl}-phosphonicacid dipropyl ester

25.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid dipropyl ester

26.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid dipropyl ester

27.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid dibenzyl ester

28.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-piperidin-4-yloxy)-phenyl]-methyl}-phosphonicacid dibenzyl ester

29.((7-Carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-pyrrolidin-3-yloxy]-phenyl}-methyl)-phosphonicacid dibenzyl ester

30.{(7-Carbamimidoyl-naphthalen-2-yloxy)-[4-(1-carbamimidoyl-pyrrolidin-3-yloxy)-phenyl]-methyl}-phosphonicacid dibenzyl ester

EXAMPLE 1(7-Carbamimidoyl-naphthalen-2-yloxy)-[{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonicacid diethyl ester-dihydrochloride

1. 4-(4-Formyl-phenoxy)-piperidine-l-carboxylic acid tert-butyl ester

A solution of 4.9 g (0.040 mol) 4-hydroxy-benzaldehyde, 10.0 g (0.050mol) 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester(analogously to K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth.Commun. 1985, 15, 587-598) and 13.1 g (0.050 mol) triphenylphosphine in200 ml tetrahydrofuran is mixed at 5° C. with 7.9 ml (0.050 mol)azodicarboxylic acid diethyl ester and stirred for 24 hours at roomtemperature. After concentration the residue is purified bychromatography on a silica gel column (mobile solvent: isohexane/ethylacetate 8:2, 7:3). After concentrating the appropriate column fractionsone obtains 18.4 g (85%) of the title compound as a yellowish solidsubstance. Melting point. 63-64° C.; EI-MS: 305 (M⁺).

2.4-{4-Diethoxy-phosphoryl)-hydroxy-methyl]-phenoxy}-piperidine-1-carboxylicacid tert.-butyl ester

A mixture of 0.99 g (0.032 mol)4-(4-formyl-phenoxy)-piperidine-1-carboxylic acid tert.-butyl ester,0.46 ml (0.0036 mol) diethylphosphite and 0.50 ml triethylamine (0.0036mol) is heated for 4 hours to 60° C. After concentration the residue ispurified by chromatography on a silica gel column (mobile solvent: ethylacetate/methanol 19:1). After concentrating the appropriate columnfractions one obtains 1.40 g (97%) of the title compound as a viscous,colourless oil. ³¹ P-NMR: δ=23.2 ppm; EI-MS (silylated): 515 (M⁺-H+(CH₃)₃ Si).

3.4-{4-[(7-Cyano-naphthalen-2-yloxy)-(diethoxy-phosphoryl)-methyl]-phenoxy}-piperidine-1-carboxylicacid tert.-butyl ester

A solution of 1.50 g (0.0088 mol) 7-hydroxy-naphthalene-2-carbonitrile,3.93 g (0.0088 mol)4-{4-[(diethoxy-phosphoryl)-hydroxy-methyl]-phenoxy}-piperidine-1-carboxylicacid tert.-butyl ester and 3.73 g (0.0142 mol) triphenylphosphine in 150ml tetrahydrofuran is admixed at 5° C. with 2.23 ml (0.0142 mol)azodicarboxylic acid diethyl ester and stirred for 96 h at roomtemperature. After concentration the residue is purified bychromatography on a silica gel column (mobile solvent: ethylacetate/methanol 19:1). After concentrating the appropriate columnfractions one obtains 2.47 g (47%) of the title compound as a viscous,yellow oil. ³¹ P-NMR: δ=19.0 ppm.

4.7-{[4-(l-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-diethoxy-phosphoryl)}-methyloxy-naphthalene-2-carbothioamide

A solution of 1.61 g (0.0027 mmol)4-{4-[(7-cyano-naphthalen-2-yloxy)-(diethoxy-phosphoryl)-methyl]-phenoxy}-piperidine-1-carboxylicacid tert.-butyl ester and 0.75 ml (0.0054 mmol) triethylamine in 15 mlpyridine is saturated with hydrogen sulfide. It is stirred for 2 days atroom temperature, all volatile components are removed in a vacuum and1.67 g (98%) of the title compound is obtained as an orange-colouredsolid. 31P-NMR: δ=19.5 ppm; (-)-FAB-MS: 627 (M-H⁺).

5.7-{[4-(1-Tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-(diethoxy-phosphoryl)}-methyloxy-naphthalene-2-carbimidothionicacid methyl ester hydroiodide

A solution of 1.56 g (0.0025 mol)7-{[4-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-(diethoxy-phosphoryl)}-methyloxy-naphthalen-2-carbothioamidein 15 ml acetone is admixed with 0.77 ml (0.012 mol) methyl iodide andstirred for 24 h at room temperature in the absence of light. Allvolatile components are removed in a vacuum and 2.38 g of the titlecompound is obtained as a yellow solid (³¹ P-NMR: δ=19.2 ppm). The crudeproduct is reacted further without purification.

6.7-{[4-(Piperidin-4-yloxy)-phenyl]-(diethoxy-phosphoryl)}-methyloxy-naphthalene-2-carbamidine-dihydrochloride

A mixture of 2.27 g (0.003 mmol)7-{[4-(1-tert-butoxycarbonyl-piperidin-4-yloxy)-phenyl]-(diethoxy-phosphoryl)}-methyloxy-naphthalene-2-carbimidothionicacid methyl ester hydroiodide and 0.68 g (0.0089) ammonium acetate in 20ml methanol is heated for 24 hours under reflux. After cooling thereaction mixture 20 ml of a diethyl ether solution saturated withhydrogen chloride is added dropwise within 4 h while cooling on ice.After removing the solvent in a vacuum the residue is dissolved in 25 mlwater, adjusted to pH 3 with 2 N HCl and chromatographed by means ofpreparative HPLC (RP-18 column, 15-25 μm) (mobile solvent: H₂ O/CH₃ OH55:45, pH 3). After concentrating the appropriate column fractions anddrying in a vacuum (10⁻² Torr), the residue is dissolved in 5 mlwater/tert-butanol mixture (1:1) and lyophilised. 0.66 g (0.0011 mol) ofthe title compound with a melting point of 278° C. is obtained as a palepink coloured solid. ³¹ P-NMR: δ=19.2 ppm; (+)-FAB-MS: 512 (M+H⁺).

7. ((7-Carbamididoyl-naphthalen-2-yloxy)-{4-[1-(1-iminoethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonic acid diethyl esterdihydrochloride

0.24 ml (1.71 mol) triethylamine is added dropwise under nitrogen at 5°C. to 42 mg acetimidic acid ethyl ester hydrochloride (0.34 mmol) and100 mg7-{[4-(piperidin-4-yloxy)-phenyl]-(diethoxy-phosphoryl)}-methyloxy-naphthalene-2-carbamidine-dihydrochloride(0.17 mmol) in 10 ml ethanol. It is stirred for 2 days at roomtemperature, concentrated by evaporation, the residue is dissolved in 10ml water, it is adjusted to pH 3 with 2 N HCl and filtered. The filtrateis chromatographed by means of preparative HPLC (RP-18 column, 15-25 μm)(mobile solvent: H₂ O, pH 3;

H₂ O/CH₃ CN 65:35, pH 3). After concentrating the appropriate columnfractions and drying in a vacuum (10⁻² Torr) 70 mg (0.11 mmol; 65%) ofthe title compound is obtained as a bright, solidified oil.(+)-FAB-MS:553 (MH⁺).

EXAMPLE 2 Description of Pharmacological Experiments

Obtaining Plasma

9 parts of fresh blood from healthy donors was mixed with one part ofsodium citrate solution (0.11 mol/l) and it was centrifuged for 10minutes at room temperature at ca. 3000 r.p.m. The plasma was removed bypipette and can be stored at room temperature for ca. 8 hours.

Activated Partial Thromboplastin Time (APTT)

100 μl citrate plasma and 100 μl APTT reagent (StagoDiagnostics/Boehringer Mannheim GmbH; contains cephalin lyophilisatewith a microcrystalline kieselguhr activator) are incubated for 3minutes at 37° C. together with 10 μl dimethylsulfoxide (DMSO) or 10 μlof a solution of the active substance in DMSO in a ball coagulometer(KC10 from the Amelung Company). On addition of 100 μl 0.025 M calciumchloride solution a stopwatch is started and the time at whichcoagulation starts is determined. The APTT is ca. 28-35 seconds in thecontrol measurements and is extended by the active substances. If nocoagulation occurred in the measurements after 5 minutes the experimentwas stopped (>300).

The measured APTT times in seconds are given in table 1 as a differenceto the control. The concentrations of the active substances in the finalvolume were 100 μM (APTT 100), 10 μM (APTT 10), 1 μM (APTT 1), 0.1 μM(APTT 0.1).

Thrombin Time

200 μl citrate plasma is incubated for 2 minutes at 37° C. in a ballcoagulometer (KC10 from the Amelung Company). 10 μl dimethylsulfoxide(DMSO) or a solution of the active substance in DMSO is added to 190 μlpre-heated thrombin reagent (Boehringer Mannheim GmbH; contains ca. 3U/ml horse thrombin and 0.0125 M Ca⁺⁺). On addition of 200 μl of thissolution to the plasma a stopwatch is started and the time at whichcoagulation starts is determined. The thrombin time is ca. 24 sec. incontrol measurements and is extended by the active substances. If nocoagulation occurred in the measurements after 5 minutes the experimentwas stopped (>300).

The measured thrombin times in seconds are given in table 1 as adifference to the control. The concentrations of the active substancesin the final volume were 500 μM (TT 500).

Inhibition Constants

The kinetic measurements were carried out at pH=7.5 and 25° C. in 0.1 Mphosphate buffer that contained 0.2 M sodium chloride and 0.5%polyethylene glycol 6000 (see below for preparation) in polystyrenesemi-microcuvettes in a total volume of 1 ml. The reactions were startedby addition of enzyme to pre-incubated solutions that contained eitherdimethyldisulfoxide (control) or solutions of the test substance in DMSO(inhibitor stock solutions: 10 mM in DMSO). The increase in absorbanceat 405 nm due to the release of p-nitroaniline from the substrate wasmonitored over a time period of 12 minutes. Measured values (absorbanceversus time) were determined at intervals of 20 seconds and these datawere stored by a computer.

The inhibition constants K_(i) were determined as follows. The rates V₀(change in absorbance per second; measurements without inhibitor) andV_(i) (change in absorbance per second; measurements with inhibitor)were determined by linear regression using only the measurement pointsin which the substrate concentration had decreased by less than 15%.K_(M) and V_(max) were determined from a measurement series (constantinhibitor concentration, variable substrate concentrations) by anon-linear fit to the equation ##EQU1##

The K_(i) value is obtained by non-linear regression from the entireseries of measurements with 16 sets of data (measurements at 4 differentsubstrate concentrations and each with 4 different inhibitorconcentrations) from the equation ##EQU2## in which V_(Max) denotes themaximum rate in the absence of an inhibitor, K_(M) denotes the Michaelisconstant and [S] the substrate concentration.

The measured K_(i) values in [μM] are stated in table 1.

FXa

Stock solution: 990 μl phosphate buffer solution (see below forpreparation) was admixed with 10 μl human factor Xa (Boehringer MannheimGmbH; 10 U; suspension) and stored on ice for a maximum of 4 hours. Forthe measurement 850 μl phosphate buffer and 100 μl substrate[N-methoxycarbonyl-(D)-norleucyl-glycyl-(L)-arginine-4-nitroaniline-acetate;Chromozyme X; Boehringer Mannheim GmbH; substrate concentrations used800, 600, 400 and 200 μM; K_(M) 400 μM] and 25 μl inhibitor solution or25 μl DMSO (control) are preheated in a photometer (25° C.). Thereaction is started by adding 25 μl stock solution.

Preparation of 0.1 M phosphate buffer solution (pH 7.5. 0.2 M NaCl)

8.90 g Na₂ HPO₄ H₂ O, 5.84 g NaCl and 2.50 g polyethylene glycol 6000are dissolved in 400 ml distilled water and filled up to a total volumeof 500 ml with distilled water (solution I). 1.36 g KH₂ PO₄, 1.17 g NaCland 0.50 g polyethylene glycol 6000 are dissolved in 80 ml distilledwater and filled up to a total volume of 100 ml with distilled water(solution II). Then sufficient solution II (ca. 85 ml) is added tosolution I for the pH value to be 7.5. The buffer solution is alwaysprepared fresh (stable for a maximum of 10 days when stored in arefrigerator at 4° C.).

                  TABLE 1                                                         ______________________________________                                        Pharmacological data for example compound 1                                   Example Ki     APTT     APTT  APTT   APTT  TT                                 No.        (fXa)                                                                               100        10                                                                                   1     0.1                                                                                 500                            ______________________________________                                        1       0.002  >300     >300  45     8     49                                 ______________________________________                                    

We claim:
 1. A compound of the formula ##STR13## wherein R¹ and R² are independently hydrogen, C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, C₁ -C₆ hydroxyalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkinyl or aralkyl which comprises a phenyl, naphthyl or biphenyl group linked to a C₁ -C₆ alkyl chain, or R¹ and R² together are an alkylene group which, together with the oxygen atoms to which it is bound and the phosphorous atom to which the oxygen atoms are bound, forms a saturated 5-membered to 8-membered ring;R³ is (a) an amino group which is unsubstituted or substituted by at least one of C₁ -C₆ alkyl, C₃ -C₈ cycloalkyl, C₁ -C₆ hydroxyalkyl, C₃ -C₆ alkenyl, C₃ -C₆ alkinyl or benzyl; (b) C₁ -C₆ alkyl, (c) C₃ -C₈ cycloalkyl or (d) an aryl residue selected from the group consisting of phenyl, biphenyl or naphthyl, which aryl residue is unsubstituted or substituted by at least one C₁ -C₆ alkyl, C₁ -C₆ alkyloxy or halogen; and n is an integer of 1 to 4; or a pharmaceutically acceptable hydrate, solvate or salt thereof, or an optically active form thereof.
 2. Compound of claim 1, wherein R¹ and R² are independently hydrogen, methyl, ethyl, propyl, alkyl, propargyl, or benzyl, or R¹ and R² together are ethylene or propylene;R¹ is amino, N-methyl amino, N-benzyl amino, N-alkyl amino, N,N-dimethylamino, menthyl, ethyl, cyclopropyl or 4-methoxyphenyl; and n is 1 or
 2. 3. Compound of claim 2, wherein R¹ and R² are both an ethyl group.
 4. Compound of claim 3, wherein R¹ is a methyl group.
 5. Compound of claim 1, wherein the compound is((7-carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonic acid diethyl ester-dihydrochloride.
 6. Pharmaceutical composition suitable for inhibiting factor Xa, comprising a factor Xa-inhibiting effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier therefor.
 7. A method for the treatment or prophylactic treatment of thrombosis, apoplexy, coronary infarction, inflammation or arteriosclerosis in a patient in need of such treatment or prophylactic treatment, comprising administering an effective amount of a compound of claim 1 to the patient.
 8. A method of inhibiting factor Xa in a patient in need of such inhibition, said method comprising administering a factor Xa-inhibiting amount of a compound of claim 1 to the patient.
 9. A method of preventing the formation of hyaline thrombi in a patient in need of such prevention, comprising administering to said patient a hyaline thrombi-preventing amount of a compound of claim
 1. 10. Method of claim 7, wherein the compound is((7-carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonic acid diethyl ester-dihydrochloride.
 11. Method of claim 8, wherein the compound is((7-carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonic acid diethyl ester-dihydrochloride.
 12. Method of claim 9, wherein the compound is((7-carbamimidoyl-naphthalen-2-yloxy)-{4-[1-(1-imino-ethyl)-piperidin-4-yloxy]-phenyl}-methyl)-phosphonic acid diethyl ester-dihydrochloride. 